Horwitz J P, Massova I, Wiese T E, Besler B H, Corbett T H
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201.
J Med Chem. 1994 Mar 18;37(6):781-6. doi: 10.1021/jm00032a010.
The present study establishes correlations of in vivo growth inhibition of a solid tumor, pancreatic ductal adenocarcinoma (Panc03), of mice with the steric and electrostatic fields and the hydrophobic parameter log P of a series (32) of 1-[[2-(dialkylamino)alkyl]amino]- 9H-thioxanthen-9-ones by the 3D-QSAR method comparative molecular field analysis (CoMFA). The template molecular model was hycanthone methanesulfonate (19), the structure of which had been established previously by X-ray crystallography. The hycanthone base is protonated at the terminal nitrogen N(2), and an intramolecular hydrogen bond is present between the proximal nitrogen N(1) and carbonyl oxygen O(1) atoms. Crystallographic data also indicate a planar arrangement of bonds around N(1). However, the molecular geometry of 19, optimized by semiempirical molecular orbital methods (PM3, MNDO, AM1), showed the expected trigonal-pyramidal configuration for N(1). A comparison of MO and ab initio methods applied to a model compound, 1-amino-9H-thioxanthen-9-one, led to the selection of PM3 as the method for full geometry optimization of first the cationic and then the neutral forms of 1-32, whereas AM1 provided atomic charges for these same structures save those incorporating a sulfonamide moiety (5, 7, 20, 25, 26, 29, 31, and 32). Acceptable values for the latter were obtained from ab initio calculations. Structures were aligned by minimizing root-mean-square (rms) differences in the fitting of structures to 19 using the FIT option of SYBYL. An alternative strategy of alignment, steric and electrostatic alignment (SEAL), was invoked to provide a comparison of statistical data generated with the rms alignment. The rms-fit alignment of structures produced slightly better cross-validated and conventional r2 values than those generated with the SEAL method. In addition, the rms-fit data indicate that a shift in the lattice of one-half of its spacing has a much smaller effect on the CoMFA data for a lattice of 1 A than one of 2 A. Inclusion of log P in a CoMFA of the neutral structures effected a small (ca. 8-10%) but significant improvement in cross-validated r2 values. The relative contributions of the hydrophobic effects and the steric and electrostatic fields to the conventional r2 values were 16%, 42%, and 42%, respectively. By contrast, incorporation of frontier molecular orbital (HOMO and LUMO) energies or their gaps in the PLS analyses failed to enhance correlation coefficients derived for either the charged or uncharged compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究通过三维定量构效关系方法——比较分子力场分析（CoMFA），建立了小鼠实体瘤胰腺导管腺癌（Panc03）的体内生长抑制与一系列（32种）1-[[2-（二烷基氨基）烷基]氨基]-9H-噻吨-9-酮的空间和静电场以及疏水参数log P之间的相关性。模板分子模型为甲磺酸海恩酮（19），其结构先前已通过X射线晶体学确定。海恩酮碱在末端氮N(2)处质子化，并且在近端氮N(1)和羰基氧O(1)原子之间存在分子内氢键。晶体学数据还表明N(1)周围键的平面排列。然而，通过半经验分子轨道方法（PM3、MNDO、AM1）优化的19的分子几何结构显示N(1)具有预期的三角锥构型。将分子轨道（MO）方法和从头算方法应用于模型化合物1-氨基-9H-噻吨-9-酮进行比较，结果选择PM3作为首先对1-32的阳离子形式然后对中性形式进行完全几何优化的方法，而AM1为这些相同结构提供原子电荷，但包含磺酰胺部分（5、7、20、25、26、29、31和32）的结构除外。后者的可接受值通过从头算计算获得。使用SYBYL的FIT选项，通过最小化结构与19拟合中的均方根（rms）差异来对齐结构。采用了一种替代的对齐策略，即空间和静电对齐（SEAL），以比较用rms对齐生成的统计数据。与SEAL方法生成的数据相比，结构的rms拟合对齐产生的交叉验证和常规r2值略好。此外，rms拟合数据表明，对于1埃的晶格，其间距一半的晶格位移对CoMFA数据的影响比对2埃晶格的影响小得多。在中性结构的CoMFA中纳入log P对交叉验证的r2值产生了小（约8 - 10%）但显著的改善。疏水效应以及空间和静电场对常规r2值的相对贡献分别为16%、42%和42%。相比之下，在偏最小二乘（PLS）分析中纳入前沿分子轨道（HOMO和LUMO）能量或其间隙未能提高带电或不带电化合物的相关系数。（摘要截断于400字）
